Recent advances in science and technology have led to a rapid aging of the population and an increased demand for medical services. Under such circumstances, the use of a larger amount of erythrocytes for transfusion has been required, causing a severe supply shortage of transfusable erythrocytes. Blood transfusion increases the risk of transfusion transmitted infections, which cause serious problems in the use of erythrocytes. Such transfusion transmitted infections include viral contamination caused by various viruses such as human immunodeficiency virus (HIV) and hepatitis type B virus, and bacterial contamination. Newly emerging pathogens responsible for many infectious diseases transmitted by blood transfusion, such as blood-borne tropical diseases and variant Creutzfeldt-Jacob disease, are attributed to an increase in overseas travel and have become serious problems.
Thus, there is a growing need for artificially produced erythrocytes (Greenwalt, T. J.; Zehner Sostok, C.; Dumaswala, U. J. Studies in red blood cell preservation. 1. Effect of the other formed elements. Vox Sang. 58:85-89; 1990; Olsson, M. L.; Clausen, H. Modifying the red cell surface: towards an ABO-universal blood supply. Br. J. Haematol. 140:3-12; 2008).
The current worldwide shortage of transfusable blood causes difficulties in the surgery and treatment of patients. In view of this situation, some researchers have made considerable efforts to produce a large amount of erythrocytes using stem cells. However, most of these efforts still remain at laboratory level where only a small amount of cells proliferate in culture wells.
A previously published report (Mountford et al. Prospects for the manufacture of red cells for transfusion. Br J Haematol. 2010, 149, 22-34) states that an important challenge for mass production of red blood cells is to increase the cell concentration. Although best results of current technology are applied to the manufacture of a single pack of red blood cells, a culture area corresponding to two tennis courts is required, as determined by an arithmetic calculation (Timmins et al. Blood cell manufacture: current methods and future challenges. Trends in Biotechnology 2009, 27, 415-422), making it practically difficult to produce red blood cells on a large scale.
Most of the studies to date have focused on the amplification of early stem cells and progenitor cells. However, little research has been conducted on the terminal maturation of cells, which is substantially the most important stage, and little is known about the reasons for and solutions to low enucleation rate and low cell viability.
As a result of research to solve the problems of the prior art and produce clinically useful concentrated erythrocytes even in a small-scale space, the present inventors have found that when erythroid cells are cultured at a high density such that the cells come into direct physical contact with each other or in the presence of ICAM-4 protein, the protein mediates binding between the erythroid cells and the resulting intercellular signal exchange is activated, achieving high productivity of erythrocytes. The present invention has been accomplished based on this finding.